Novel tetracyclic arylcarbonyl indoles having serotonin receptor affinity useful as therapeutic agents, process for their preparation and pharmaceutical composition containing them

ABSTRACT

The present invention relates to novel tetracyclic arylcarbonyl indoles, their derivatives, their analogues, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, novel intermediates described herein and pharmaceutically acceptable compositions containing them. This invention particularly relates to novel tetracyclic arylcarbonyl indoles of the general formula (I), their derivatives, their analogues, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, novel intermediates described herein and pharmaceutically acceptable compositions containing them. This invention also relates to process/es for preparing such compound/s of general formula (I), composition/s containing effective amount/s of such a compound and the use of such a compound/composition in therapy

FIELD OF INVENTION

The present invention relates to novel tetracyclic arylcarbonyl indoles,their tautomeric forms, their stereoisomers, their polymorphs, theirpharmaceutically acceptable salts, their pharmaceutically acceptablesolvates, novel intermediates described herein and pharmaceuticallyacceptable compositions containing them.

The present invention also relates to the process for preparing thecompounds of general formula (I), their tautomeric forms, theirstereoisomers, their geometric forms, their N-oxides, their polymorphs,their pharmaceutically acceptable salts, their pharmaceuticallyacceptable solvates, novel intermediates described herein andpharmaceutically acceptable compositions containing them.

The compounds of the general formula (I) of this invention are 5-HT(Serotonin) ligands e.g. agonists or antagonists.

Thus, compounds of general formula (I) of this invention are useful fortreating diseases wherein activity of 5-HT (Serotonin) is modulated toobtain the desired effect. Specifically, the compounds of this inventionare useful in the treatment and/or prophylaxis of psychosis,paraphrenia, psychotic depression, mania, schizophrenia,schizophreniform disorders, anxiety, migraine headache, depression, drugaddiction, convulsive disorders, personality disorders, hypertension,autism, post-traumatic stress syndrome, alcoholism, panic attacks,obsessive-compulsive disorders, and sleep disorders.

The compounds of general formula (I) of this invention are also usefulto treat psychotic, affective, vegetative and psychomotor symptoms ofschizophrenia and the extrapyramidal motor side effects of otherantipsychotic drugs.

The compounds of general formula (I) of this invention are also usefulto treat neurodegenerative disorders like Alzheimer's disease,Parkinsonism and Huntington's chorea and chemotherapy-induced vomiting.The compounds of general formula (I) of this invention are also usefulin modulation of eating behavior and thus are useful in reducing themorbidity and mortality associated with excess weight.

BACKGROUND OF THE INVENTION

Many diseases of the central nervous system are influenced by theadrenergic, the dopaminergic and the serotenergic neurotransmittersystems. Serotonin has been implicated in a number of diseases andconditions, which originate in the central nervous system. These includediseases and conditions related to sleeping, eating, perceiving pain,controlling body temperature, controlling blood pressure, depression,anxiety, schizophrenia and other bodily states. (References: Fuller, R.W., Drugs Acting on Serotonergic Neuronal Systems, Biology ofSerotonergic Transmission, John Wiley & Sons Ltd. (1982), 221-247;Boullin D. J., Serotonin in Mental abnormalities (1978), 1, 316; BarchasJ. et. al., Serotonin and Behavior (1973)). Serotonin also plays animportant role in the peripheral systems, such as the gastrointestinalsystem, where it has been found to mediate a variety of contractile,secretory and electrophysiologic effects.

Due to the broad distribution of serotonin within the body, there is lotof interest and use, in the drugs that affect serotonergic systems.Particularly, preferred are the compounds which have receptor specificagonism and/or antagonism for the treatment of a wide range ofdisorders, including anxiety, depression, hypertension, migraine,obesity, compulsive disorders, schizophrenia, autism, neurodegenerativedisorders like Alzheimer's disease, Parkinsonism and Huntington's choreaand chemotherapy-induced vomiting (References: Gershon M. D. et. al.,The peripheral actions of 5-Hydroxytryptamine (1989), 246; Saxena P. R.et. al., Journal of Cardiovascular Pharmacology (1990), supplement 7,15).

The major classes of serotonin receptors (5-HT₁₋₇) contain fourteen toeighteen separate receptors that have been formally classified(References: Glennon et al, Neuroscience and Behavioral Reviews (1990),14, 35 and Hoyer D. et al, Pharmacol. Rev. (1994), 46, 157-203).Recently discovered information regarding sub-type identity,distribution, structure and function suggests that it is possible toidentify novel, sub-type specific agents having improved therapeuticprofiles with lesser side effects. The 5-HT₆ receptor was identified in1993 (References: Monsma et al, Mol. Pharmacol. (1993), 43, 320 327 andRuat M. et al, Biochem. Biophys. Res. Com. (1993), 193, 269-276).Several antidepressants and atypical antipsychotics bind to the 5-HT₆receptor with high affinity and this binding may be a factor in theirprofile of activities (References: Roth et al, J. Pharm. Exp. Therapeut.(1994), 268, 1403-1410; Sleight et al, Exp. Opin. Ther. Patents (1998),8, 1217-1224; Bourson et al, Brit. J. Pharmacol. (1998), 125, 1562-1566;Boess et al, Mol. Pharmacol., 1998, 54, 577-583; Sleight et al., Brit.J. Pharmacol. (1998), 124, 556-562). In addition, 5-HT₆ receptor hasbeen linked to generalized stress and anxiety states (Reference:Yoshioka et al, Life Sciences (1998), 17/18, 1473-1477). Together thesestudies and observations suggest that compounds that antagonize the5-HT₆ receptor will be useful in treating various disorders of thecentral nervous system.

U.S. Pat. No. 4,839,377 and U.S. Pat. No. 4,855,314 refer to5-substituted 3-aminoalkyl indoles. The compounds are said to be usefulfor the treatment of migraine.

British Patent 2,035,310 refers to 3-aminoalkyl-1H-indole-5-thioamidesand carboxamides. The compounds are said to be useful in treatinghypertension, Raymond's disease and migraine.

European Patent Publication 303,506 refers to3-polyhydropyridyl-5-substituted-1H-indoles. The compounds are said tohave 5-HT, receptor agonists and vasoconstrictor activity and to beuseful in treating migraine. European Patent Publication 354,777 refersto N-piperidinylindolylethyl-alkane sulfonamide derivatives. Thecompounds are said to be 5-HT, receptor agonists and havevasoconstrictor activity and are useful in treating cephalic pain.

European Patent Publication 438,230, refers to indole-substitutedfive-membered heteroaromatic compounds. The compounds are said to have“5-HT₁-like” receptor agonist activity and to be useful in the treatmentof migraine and other disorders for which a selective agonist of thesereceptors is indicated.

European Patent Publication 313,397 refers to 5-heterocyclic indolederivatives. The compounds are said to have exceptional properties forthe treatment and prophylaxis of migraine, cluster headache and headacheassociated with vascular disorders. These compounds are also said tohave exceptional “5-HT₁-like” receptor agonism.

International Patent Publication WO 91/18897, refers to 5-heterocyclicindole derivatives. The compounds are said to have exceptionalproperties for the treatment and prophylaxis of migraine, clusterheadache, and headache associated with vascular disorders. Thesecompounds are also said to have exceptional “5-HT₁-like” receptoragonism.

European Patent Publication 457,701 refers to aryloxy amine derivativesas having high affinity for 5-HT_(1D) serotonin receptors. Thesecompounds are said to be useful for treating diseases related toserotonin receptor dysfunction, for example, migraine.

European Patent Publication 497,512 A2, refers to a class of imidazole,triazole and tetrazole derivatives which are selective agonists for“5-HT₁-like” receptors. These compounds are said to be useful fortreating migraine and associated disorders.

International Patent Publication WO 93/00086, describes a series oftetrahydrocarbazole derivatives, as 5-HT, receptor agonists, useful forthe treatment of migraine and related conditions.

International Patent Publication WO 93/23396, refers to fused imidazoleand triazole derivatives as 5-HT, receptor agonists, for the treatmentof migraine and other disorders.

Schoeffter P. et al. refer to methyl4-{4-[4-(1,1,3-trioxo-2H-1,2-benzoisothiazol-2-yl)butyl]-1-piperazinyl}1H-indole-3-carboxylateas a selective antagonist for the 5-HTIA receptor in their paper“SD2216-525, a selective and potent 5-HT_(1A) receptor antagonist”European Journal of Pharmacology, 244, 251-257 (1993).

International Patent Publication WO 94/06769, refers to2-substituted-4-piperazine benzothiophene derivatives that are serotonin5-HT_(1A) and 5-HT_(1D) receptor agents useful in the treatment ofanxiety, depression, migraine, stroke, angina and hypertension.

SUMMARY OF THE INVENTION

The present invention relates to novel tetracyclic arylcarbonyl indoles,their tautomeric forms, their stereoisomers, their polymorphs, theirpharmaceutically acceptable salts, their pharmaceutically acceptablesolvates, novel intermediates described herein and pharmaceuticallyacceptable compositions containing them.

More particularly, the present invention relates to novel tetracyclicarylcarbonyl indoles of the general formula (I), their tautomeric forms,their stereoisomers, their polymorphs, their pharmaceutically acceptablesalts, their pharmaceutically acceptable solvates, novel intermediatesdescribed herein and pharmaceutically acceptable compositions containingthem and use of these compounds in medicine.

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁ and R₁₂ may be sameor different and each independently represent hydrogen, halogen,perhaloalkyl, substituted or unsubstituted groups such as linear orbranched (C₁-C₃)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₃)alkoxy,cyclo(C₃-C₇)alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,acyl, acyloxy, acylamino, monoalkylamino, dialkylamino, hydroxyalkyl,alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, sulfonic acids andits derivatives.

R₁₃ and R₁₄ may be same or different and each independently representshydrogen, substituted or unsubstituted groups such as linear or branched(C₁-C₃)alkyl, (C₃-C₇)cycloalkyl, optionally R₁₃ and R₁₄ along with thenitrogen atom, may form a 6 or 7-membered heterocyclic ring, wherein thering may be further substituted, and it may have either one, two orthree double bonds or “additional heteroatoms”, as defined above.

“n” is an integer ranging from 1 to 2. It is preferred that n be 1.

Partial List of Such Compounds of General Formula (I) is as Follows:

-   11-(2-N,N-Dimethylaminoethyl)isoindolo[2,1-a]indol-6-one;-   11-[(2-N,N-Dimethylamino)ethyl]-2-fluoroisoindolo[2,1-a]indol-6-one;-   11-[(2-N,N-Dimethylamino)ethyl]-2-fluoroisoindolo[2,1-a]indol-6-one    hydrochloride salt;-   11-[(2-N,N-Dimethylamino)ethyl]-2-fluoroisoindolo[2,1-a]indol-6-one    maleic acid salt;-   11-[(2-N,N-Dimethylamino)ethyl]2-fluoroisoindolo[2,1-a]indol-6-one    D, L-malic acid salt;-   11-[(2-N,N-Dimethylamino)ethyl]-2-fluoroisoindolo[2,1-a]indol-6-one    oxalate salt;-   11-[(2-N,N-Dimethylamino)ethyl]-2-fluoroisoindolo[2,1-a]indol-6-one    citrate salt;-   11-[(2-N-cyclopropyl-N-methylamino)ethyl]-2-fluoroisoindoto[2,1-a]indol-6-one;-   11-[(2-N-cydopropylethyl]-2-fluoroisoindolo[2,1-a]indol-6-one;-   2-Bromo-11-[(2-N,N-dimethylamino)ethyl]isoindolo[2,1-a]indol-one;-   2-Chloro-11-[(2-N,N-dimethylamino)ethyl]isoindolo[2,1-a]indol-6-one;-   4-Chloro-11-[(2-N,N-dimethylamino)ethyl]isoindolo[2,1-a]indol-6-one;-   11-[(2-N,N-Dimethylamino)ethyl]-2-methylisoindolo[2,1-a]indol-6-one;-   11-[(2-N,N-Dimethylamino)ethyl]-2-methoxyisoindolo[2,1-a]indol-6-one;-   11-[(2-N,N-Dimethylamino)ethyl]Amethoxyisoindolo[2,1-a]indol-6-one;-   11-[(2-N,N-Dimethylamino)ethyl]-4-trifuoromethylisoindololo[2,1-a]indol-6-one;-   11-[(2-N,N-Dimethylamino)ethyl]ethylisoindolo[2,1-a]indol-6-one;-   11-[(2-N,N-Dimethylamino)ethyl]-2,4-difluoroisoindolo[2,1-a]indol-6-one;-   2,4-Dichloro-11-[(2-N,N-dimethylamino)ethyl]isoindolo[2,1-a]indol-6-one;-   3,4-Dichloro-11-[(2-N,N-dimethylamino)ethyl]jsoindolo[2,1-a]indol-6-one;-   1,2,4-Trichloro-11-[(2-N,N-dimethylamino)ethyl]isoindolo[2,1-a]indol-6-one;-   11-[(2-N,N-Dimethylamino)ethyl]-2,4-dimethylisoindolo[2,1-a]indol-6-one;-   11-[(2-N,N-Dimethylamino)ethyl]-3,4-dimethylisoindolo[2,1-a]indol-6-one;-   1-Chloro-11-[(2-N,N-dimethylamino)ethyl]-4-methylisoindolo[2,1-a]indol-6-one;-   3-Chloro-11-[(2-N,N-dimethylamino)ethylqmethylisoindolo[2,1-a]indol-6-one;-   11-[(2-N,N-Dimethylamino)propyl]-4-methylisoindolo[2,1-a]indol-6-one;-   3-Chloro-11-[(2-N-methylamino)ethyl]methylisoindolo[2,1-a]indol-6-one;-   3-Chloro-11-[(2-N-methyl-N-acetylamino)ethyl]Amethylisoindolo[2,1-a]indol-6-one;-   3-Chloro-11-[(2-N-methylamino)ethyl]-2-methoxyisoindolo[2,1-a]indol-6-one;-   3-Chloro-11-[(2-N-methylamino)ethyl]-2-sulfoamidoisoindolo[2,1-indol-6-one;-   3-Iodo-11-[(2-N-methylamino)ethyl]-2-methoxyisoindolo[2,1-a]indol-6-one;-   2-Bromo-11-[(2-morpholin-1-yl)ethyl]isoindolo[2,1-a]indol-6-one;-   2-Bromo-11-[2-(4-methylpiperazin-1-yl)ethyl]isoindolo[2,1-a]indol-6-one;    and its stereoisomers, its N-oxides, its polymorphs, its    pharmaceutically acceptable salts and solvates.

The present invention also envisages some useful bio-active metabolitesof the compounds of general formula (I).

The compounds of general formula (I) of this invention are useful in thetreatment and/or prophylaxis of a condition wherein modulation of 5-HTactivity is desired.

The present invention provides for use of the compounds of generalformula (I) according to above, for the manufacture of the medicamentsfor the potential use in the treatment and/or prophylaxis of certain CNSdisorders such as, anxiety, depression, convulsive disorders,obsessive-compulsive disorders, migraine headache, cognitive memorydisorders e.g. Alzheimer's disease and age-related cognitive decline,ADHD (Attention Deficient Disorder/Hyperactivity Syndrome), personalitydisorders, psychosis, paraphrenia, psychotic depression, mania,schizophrenia, schizophreniform disorders, withdrawal from drug abusesuch as cocaine, ethanol, nicotine and benzodiazepines, panic attacks,sleep disorders (including disturbances of Circadian rhythm) and alsodisorders associated with spinal trauma and/or head injury such ashydrocephalus. Compounds of the invention are further expected to be ofuse in the treatment of mild cognitive impairment and otherneurodegenerative disorders like Alzheimer's disease, Parkinsonism andHuntington's chorea.

The compounds of the invention are also expected to be of use in thetreatment of certain GI (Gastrointestinal) disorders such as IBS(Irritable bowel syndrome) or chemotherapy induced emesis.

The compounds of the invention are also expected to be of use in themodulation of eating behavior and these compounds can also be used toreduce morbidity and mortality associated with the excess weight.

The present invention provides a method for the treatment of a human ora animal subject suffering from certain CNS disorders such as, anxiety,depression, convulsive disorders, obsessive-compulsive disorders,migraine headache, cognitive memory disorders e.g. Alzheimer's diseaseand age-related cognitive decline, ADHD (Attention DeficientHyperactivity Disorder), personality disorders, psychosis, paraphrenia,psychotic depression, mania, schizophrenia, schizophreniform disorders,withdrawal from drug abuse such as cocaine, ethanol, nicotine andbenzodiazepines, panic attacks, sleep disorders (including disturbancesof Circadian rhythm) and also disorders associated with spinal traumaand/or head injury such as hydrocephalus. Compounds of the invention arefurther expected to be of use in the treatment of mild cognitiveimpairment and other neurodegenerative disorders like Alzheimer'sdisease, Parkinsonism and Huntington's chorea.

The present invention also provides a method for modulating 5-HTreceptor function desired in certain cases.

The present invention also includes a isotopically-labelled compounds,which are identical to those defined in the general formula (I), but forthe fact that one or more atoms are replaced by an atom having an atomicmass or mass number different from the atomic mass or mass number foundusually in nature. Examples of isotopes that can be incorporated intocompounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, fluorine, chlorine, iodine, bromine and mTecnitium, exemplified by 2H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁸F,^(99m)Tc ³¹P, S, ¹²³I and ¹²⁵I. Compounds of present invention andpharmaceutically acceptable salts and prodrugs of said compounds thatcontain the aforementioned isotopes and/or other isotopes of other atomsare within the scope of this invention.

Isotopically labelled compounds of the present invention are useful indrug and/or substrate tissue distribution and target occupancy assays.For example, isotopically labelled compounds are particularly useful inSPECT (single photon emission computed tomography) and in PET (positronemission tomography).

An effective amount of a compound of general formula (I) or its salt isused for producing medicaments of the present invention, along withconventional pharmaceutical auxiliaries, carriers and additives.

The present invention also relates to a pharmaceutical composition fortreating and/or prophylaxis of disorders, a condition wherein modulationof 5-HT is desired in a mammal, comprising:

-   -   a. a pharmaceutically acceptable carrier    -   b. a compound of general formula (I) as defined above, and    -   c. a 5-HT re-uptake inhibitor, or its pharmaceutically        acceptable salt;    -   wherein the amounts of each active compound (a compound of        general formula (I) and a 5-HT re-uptake inhibitor), is such        that the combination is effective in treating such a condition.

The present invention also relates to a method of treatment and/orprophylaxis of disorders, a condition wherein modulation of 5-HT isdesired in a mammal, comprising:

-   -   a. a pharmaceutically acceptable carrier    -   b. a compound of general formula (I) as defined above, and    -   c. a 5-HT re-uptake inhibitor, or its pharmaceutically        acceptable salt;    -   wherein the amounts of each active compound (a compound of        general formula (I) and a 5-HT re-uptake inhibitor), is such        that the combination is effective in treating such a condition.

The present invention also relates to a pharmaceutical composition fortreating and/or prophylaxis of disorders, a condition wherein modulationof 5-HT is desired in a mammal, comprising:

-   -   a. a pharmaceutically acceptable carrier    -   b. a compound of general formula (I) as defined above, and    -   c. a melatonergic ligand, or its pharmaceutically acceptable        salt;    -   wherein the amounts of each active compound (a compound of        general formula (I) and a melatonergic ligand), is such that the        combination is effective in treating such a condition.

The present invention also relates to a method of treatment and/orprophylaxis of disorders, a condition wherein modulation of 5-HT isdesired in a mammal, comprising:

-   -   a. a pharmaceutically acceptable carrier    -   b. a compound of general formula (I) as defined above, and    -   c. a melatonergic ligand, or its pharmaceutically acceptable        salt;    -   wherein the amounts of each active compound (a compound of        general formula (I) and a melatonergic ligand), is such that the        combination is effective in treating such a condition.

The present invention also relates to a process for the preparation ofthe above said compounds, their tautomeric forms, their stereoisomers,their geometric forms, their N-oxides, their polymorphs, theirpharmaceutically acceptable salts, their pharmaceutically acceptablesolvates, novel intermediates described herein and pharmaceuticalcompositions containing them.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to novel tetracyclic arylcarbonyl indoles,their tautomeric forms, their stereoisomers, their polymorphs, theirpharmaceutically acceptable salts, their pharmaceutically acceptablesolvates, novel intermediates described herein and pharmaceuticallyacceptable compositions containing them.

More particularly, the present invention relates to novel tetracyclicarylcarbonyl indoles of the general formula (I), their tautomeric forms,their stereoisomers, their polymorphs, their pharmaceutically acceptablesalts, their pharmaceutically acceptable solvates, novel intermediatesdescribed herein and pharmaceutically acceptable compositions containingthem and use of these compounds in medicine.

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁ and R₁₂ may be sameor different and each independently represent hydrogen, halogen,perhaloalkyl, substituted or unsubstituted groups such as linear orbranched (C₁-C₃)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₃)alkoxy,cyclo(C₃-C₇)alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,acyl, acyloxy, acylamino, monoalkylamino, dialkylamino, hydroxyalkyl,alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, sulfonic acids andits derivatives,

-   -   R₁₃ and R₁₄ may be same or different and each independently        represents hydrogen, substituted or unsubstituted groups such as        linear or branched (C₁-C₃)alkyl, (C₃-C₇)cycloalkenyl, optionally        R₁₃ and R₁₄ along with the nitrogen atom, may form a 6 or        7-membered heterocyclic ring, wherein the ring may be further        substituted, and it may have either one, two or three double        bonds or “additional heteroatoms”, as defined above.

“n” is an integer ranging from 1 to 2. It is preferred that n be 1.

Suitable groups represented by R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀,R₁₁ and R₁₂ may be a halogen atom such as fluorine, chlorine, bromine oriodine; perhaloalkyl particularly perhalo(C₁-C₃)alkyl such asfluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl,fluoroethyl, difluoroethyl and the like; linear or branched (C₁-C₃)alkylgroup, such as methyl, ethyl, n-propyl, isopropyl, cyclo(C₃-C₇)alkylgroup such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl; (C₁-C₃)alkoxy group such as methoxy, ethoxy, propyloxy,iso-propyloxy; cyclo(C₃-C₇)alkoxy group such as cyclopropyloxy,cyclobutyloxy, cydopentyloxy, cyclohexyloxy, cycloheptyloxy and thelike; aryl group such as phenyl or naphthyl, aralkyl group such asbenzyl, phenethyl, C₆H₅CH₂CH₂CH₂, naphthylmethyl and the like, thearalkyl group may be substituted and the substituted aralkyl is a groupsuch as CH₃C₆H₄CH₂, Hal-C₆H₆CH₂, CH₃OC₆H₄CH₂, CH₃OC₆H₄CH₂CH₂ and thelike; aralkoxy group such as benzyloxy, phenethyloxy, naphthylmethyloxy,phenylpropyloxy and the like, the aralkoxy group may be substituted;acyl groups such as acetyl, propionyl or benzoyl, the acyl group may besubstituted; acyloxy group such as CH₃COO, CH₃CH₂COO, C₆H₅COO and thelike which may optionally be substituted, acylamino group such asCH₃CONH, CH₃CH₂CONH, C₃H₇CONH, C₆H₅CONH which may be substituted,(C₁-C₃)monoalkylamino group such as CH₃NH, C₂H₅NH, C₃H₇NH and the like,which may be substituted, (C₁-C₃)dialkylamino group such as N(CH₃)₂,CH₃(C₂H₅)N and the like, which may be substituted; alkoxyalkyl groupsuch as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl and thelike, which may be substituted; aryloxyalkyl group such as C₆H₅OCH₂,C₆H₅OCH₂CH₂, naphthyloxymethyl and the like, which may be substituted;aralkoxyalkyl group such as C₆H₅CH₂OCH₂, C₆H₅CH₂OCH₂CH₂ and the like,which may be substituted; (C₁-C₆)alkylthio, sulfonic acid or itsderivatives such as SO₂NH₂, SO₂NHCH₃, SO₂N(CH₃)₂, SO₂NHCF₃,SO₂NHCO(C₁-C₆)alkyl, SO₂NHCOaryl where the aryl group is as definedearlier and the sulfonic acid derivatives may be substituted; phosphoricacid and its derivatives such as P(O)(OH)₂, P(O)(OC₁-C₆-alkyl)₂,P(O)(O-aryl)₂ and the like.

Suitable cyclic structures formed by the two adjacent groups like R₁ andR₂ or R₂ and R₃ or R₃ and R₄ or R₅ and R₆ or R₆ and R₇ or R₇ and R₈together with carbon atoms to which they are attached may form a five ora six membered ring, which may further optionally contain one or moredouble bonds and/or one or more heteroatoms such as the group “Oxygen”,“Nitrogen”, “Sulfur” or “Selenium” or a combination of one or moredouble bonds and hetero atoms the cyclic structures may be optionallysubstituted phenyl, naphthyl, pyridyl, furanyl, thienyl, pyrrolyl,imidazolyl, pyrimidinyl, pyrazinyl and the like. Suitable substituentson the cyclic structure formed by R₁ and R₂ or R₂ and R₃ or R₃ and R₄ orR₅ and R₆ or R₆ and R₇ or R₇ and R₈ together with the adjacent carbonatoms to which they are attached include oxo, hydroxy, halogen atom suchas chlorine, bromine and iodine; nitro, cyano, amino, formyl,(C₁-C₃)alkyl, (C₁-C₃)alkoxy, thioalkyl, alkylthio phenyl or benzylgroups.

R₁₃ and R₁₄ represents hydrogen, substituted or unsubstituted linear orbranched (C₁-C₁₂)alkyl such as methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, pentyl, hexyl, octyl and the like; (C₂-C₁₂)alkanoylsuch as acetyl, propanoyl and the like; aryl group such as phenyl ornaphthyl, the aryl group may be substituted; cyclo(C₃-C₇)alkyl groupsuch as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,the cycloalkyl group may be substituted; the aralkyl group may besubstituted and the substituted aralkyl is a group such as CH₃C₆H₄CH₂,Hal-C₆H₄CH₂, CH₃OC₆H₄CH₂, CH₃OC₆H₄CH₂CH₂ and the like;(C₃-C₇)cycloheteroalkyl with heteratoms like “Oxygen”, “Nitrogen”,“Sulfur” or “Selenium” optionally containing one or two, multiple bondssuch as double or triple bonds. Suitable hetero cyclic rings formedbetween R₁₃ and R₁₄ along with “Nitrogen atom” be such as pyrrolyl,pyrrolidinyl, piperidinyl, pyridine, 1,2,3,4-Tetrahydro-pyridine,imidazolyl, pyrimidinyl, pyrazinyl, piperazinyl, diazolinyl and thelike; the heterocyclyl group may be substituted; heteroaryl group suchas pyridyl, imidazolyl, tetrazolyl and the like, the heteroaryl groupmay be substituted; heterocyclo(C₁-C₆)alkyl, such as pyrrolidinealkyl,piperidinealkyl, morpholinealkyl, thiomorpholinealkyl, oxazolinealkyland the like, the heterocyclo(C₁-C₆)alkyl group may be substituted;heteroaralkyl group such as furanmethyl, pyridinemethyl, oxazolemethyl,oxazolethyl and the like, the heteroaralkyl group may be substituted;heteroaryloxy, heteroaralkoxy, heterocycloalkoxy, wherein heteroaryl,heteroaralkyl, heterocycloalkyl and heterocyclylalkyl moieties are asdefined earlier and may be further substituted.

In the case of the compounds of general formula (I) having an asymmetriccarbon atom the present invention relates to the D-form, the L-form andD,L-mixtures and in the case of a number of asymmetric carbon atoms, thediastereomeric forms and the invention extends to each of thesestereoisomeric forms and to mixtures thereof including racemates. Thosecompounds of general formula (I) which have an asymmetric carbon and asa rule are obtained as racemates can be separated one from the other bythe usual methods, or any given isomer may be obtained by stereospecificor asymmetric synthesis. However, it is also possible to employ anoptically active compound from the start, a correspondingly opticallyactive or diastereomeric compound then being obtained as the finalcompound.

In the case of the compounds of general formula (I), where tautomerismmay exist, the present invention relates to all of the possibletautomeric forms and the possible mixture thereof.

In the case of the compounds of general formula (I) containing geometricisomerism the present invention relates to all of these geometricisomers.

Suitable pharmaceutically acceptable acid addition salts of compounds ofthe general formula (I) can be prepared of the aforementioned basecompounds of this invention are those which form non-toxic acid additionsalts, includes, salts containing pharmacologically acceptable anions,such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate,bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acidcitrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate,saccharate, benzoate, methanesulfonate, ethanesulfonate,benezenesulfonate, p-tolunesulfonate, palmoate and oxalate.

Suitable pharmaceutically acceptable base addition salts of compounds ofthe general formula (I) can be prepared of the aforementioned acidcompounds of this invention are those which form non-toxic base additionsalts, includes, salts containing pharmaceutically acceptable cations,such as lithium, sodium, potassium, calcium and magnesium, salts oforganic bases such as lysine, arginine, guanidine, diethanolamine,choline, tromethamine and the like; ammonium or substituted ammoniumsalts.

Pharmaceutically acceptable salts forming part of this invention areintended to define but not limited to the above list.

In addition, pharmaceutically acceptable salts of the compound offormula (I) can be obtained by converting derivatives which havetertiary amino groups into the corresponding quarternary ammonium saltsin the methods known in the literature by using quarternizing agents.Possible quarternizing agents are, for example, alkyl halides such asmethyl iodide, ethyl bromide and n-propyl chloride, including arylalkylhalides such as benzyl chloride or 2-phenylethyl bromide.

In the addition to pharmaceutically acceptable salts, other salts areincluded in the invention. They may serve as intermediates in thepurification of the compounds, in the preparation of other salts, or inthe identification and characterization of the compounds orintermediates.

The pharmaceutically acceptable salts of compounds of formula (I) mayexists as solvates, such as with water, methanol, ethanol,dimethylformamide, ethyl acetate, and the like. Mixtures of suchsolvates can also be prepared. The source of such solvate can be fromthe solvent of crystallization, inherent in the solvent preparation orcrystallization, or adventitious to such solvent. Such solvates arewithin the scope of this invention.

The invention also encompasses the pharmaceutically acceptable prodrugsof the compounds of the formula (I). A prodrug is a drug which has beenchemically modified and may be biologically in-active at the site ofaction, but which may be degraded or modified by one or more enzymaticor other in-vivo processes to the parent form. This prodrug should havea different pharmacokinetic profile than the parent, enabling easierabsorption across the mucosal epithelium, better salt formation, orsolubility, and/or improved systemic stability (an increase in theplasma half-life, for example). Typically, such chemical modificationsinclude the following:

-   -   1. ester or amide derivatives which may be cleaved by esterases        or lipases;    -   2. peptides which may be recognized by specific or non-specific        proteases; or    -   3. derivatives that accumulate at a site of action through        membrane selection of a prodrug from or a modified prodrug form;        or any combination of 1 to 3, above.

Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in H. Bundgard, Designof prodrugs, (1985).

Compounds of general formula (I) can be prepared by any of the methodsdescribed below. The present invention also provides processes forpreparing compounds of general formula (I) as defined above, theirderivatives, their analogs, their tautomeric forms, their stereoisomers,their geometric forms, their polymorphs, their pharmaceuticallyacceptable salts and their pharmaceutically acceptable solvates, novelintermediates described herein, where R₁, R₂. R₃, R₄, R₅, R₆, R₇, R₈,R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ and ‘n’ are as defined previously can beprepared by any of the methods described below:

Scheme - 1

Compounds of general formula (I), may be prepared by cyclizing anovel-intermediate of formula (II) given below,

wherein X is halogen such chloro, bromo or iodo, R₁, R₂, R₃, R₄, R₅, R₆,R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ and “n” are as defined previously,using a Pd(0) or Pd (II) derivative as a catalyst, for example tetrakistriphenylphosphine palladium, (Bis-tri-o-tolylphosphine) palladium andthe like; and thereafter if necessary:

-   -   i) converting a compound of the formula (I) into another        compound of the formula (I); and/or    -   ii) removing any protecting groups; and/or    -   iii) forming a pharmaceutically acceptable salt, solvate,        polymorph or prodrug thereof.

This cyclization reaction can be achieved using variety of palladiumcatalysts. The reaction may be affected in the presence of a base suchas CH₃COOK. This reaction may be carried out in the presence of solventssuch as THF, DMF, DMSO, DMA, DME, acetone and the like and preferablyusing Dimethylacetamide. The inert atmosphere may be maintained by usinginert gases such as N₂, Ar or He. The reaction temperature may rangefrom 50° C. to 200° C. based on the choice of solvent and preferably ata temperature of 160° C. The duration of the reaction may range from 1to 24 hours, preferably from 10 to 20 hours.

Scheme - 2

Compounds of general formula (I), may be prepared by reacting a compoundof formula (III) given below,

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂ and “n” are asdefined previously, with a suitable alkylating agent such as R₁₃ X orR₁₄ X or XR₁₃R₁₄X in successive steps or in one step, wherein X is goodleaving group such as halogen, hydroxyl and the like; and thereafter ifdesired or necessary carrying out steps (i), (ii) and/or (iii) asdescribed above.

The reaction is preferably carried in an organic solvent inert to theconditions of the reaction, such as acetone, THF or DMF and the like ormixtures thereof. The inert atmosphere may be maintained by using inertgases such as N₂, Ar or He. The reaction may be affected in the presenceof a base such as K₂CO₃, Na₂CO₃, TEA or mixtures thereof. The reactiontemperature may range from 20° C. to 200° C. based on the solventemployed and preferably at a temperature in the range from 30° C. to150° C. The duration of the reaction may range from 1 to 24 hours,preferably from 2 to 6 hours.

Scheme - 3

Compounds of general formula (I), may be prepared by reacting a compoundof formula (IV) given below,

-   -   wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈ and “n” are as defined        previously, with formaldehyde and a compound of formula (V)        given below,        NHR₁₃R₁₄  (V)        wherein R₁₃ and R₁₄ are as defined earlier; and thereafter if        desired or necessary carrying out steps (i), (ii) and/or (iii)        as described above.

The above reaction is preferably carried out at a temperature of 50° C.to 150° C. The formaldehyde can be in the form of as aqueous solutioni.e. 40% formalin solution, or a polymeric form of formaldehyde such asparaformaldehyde or trioxymethylene. When such polymeric forms are used,a molar excess of mineral acid, for example hydrochloric acid, is addedto regenerate the free aldehyde from the polymer. The reaction ispreferably carried in an organic solvent inert to the conditions of thereaction, such as methanol, ethanol or 3-methylbutanol and the like or amixture thereof, and preferably using either acetone or DMF. The inertatmosphere may be maintained by using inert gases such as N₂, Ar or He.The reaction temperature may range from 20° C. to 150° C. based on thechoice of solvent and preferably at a temperature in the range from 30°C. to 100° C. The duration of the reaction may range from 1 to 24 hours,preferably from 2 to 6 hours.

Scheme - 4

Compounds of general formula (I), may be prepared from another compoundof formula (I) containing —C(═O) group/s in the side chain, by knownmethods of reduction to the corresponding —C(OH, H) or —C(H, H)compound; and thereafter if desired or necessary carrying out steps (i),(ii) and/or (iii) as described above.Novel intermediates of general formula (IV) are presented as givenbelow,

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇ and R₈ are as may be same ordifferent and each independently represent hydrogen, halogen,perhaloalkyl, substituted or unsubstituted groups such as linear orbranched (C₁-C₃)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₃)alkoxy,cyclo(C₃-C₇)alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,acyl, acyloxy, acylamino, monoalkylamino, dialkylamino, hydroxyalkyl,alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, sulfonic acids andits derivatives.

The present invention also provides method to prepare intermediate bygeneral formula (IV), which comprises of cyclizing compounds of formula(VIII),

wherein R₁; R₂. R₃, R₄, R₅, R₆, R₇ and R₈ are as defined above; X ishalogeno such as chloro, bromo or iodo, using a Pd(0) or Pd (II)derivative as a catalyst, for example tetrakis triphenylphosphinepalladium, (Bis-tri-o-tolyphosphin) palladium and the like in a suitablesolvent.

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, Ed J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. For example, suitable protecting groups for thepiperazine group include BOC, COCCl₃, COCF₃. The protecting groups maybe removed according to the standard procedures.

The protecting groups may be removed at a convenient subsequent stageusing methods known from the art.

The compounds of the present invention may contain one or moreasymmetric centers and therefore they also exist as stereoisomers. Thestereoisomers of the compounds of the present invention may be preparedby one or more ways presented below.

-   -   i) One or more of the reagents may be used in their optically        active form.    -   ii) Optically pure catalyst or chiral ligands along with metal        catalyst may be employed in the reduction process. The metal        catalyst may be Rhodium, Ruthenium, Indium and the like. The        chiral ligands may preferably be chiral phosphines (Principles        of Asymmetric synthesis, J. E. Baldwin Ed., Tetrahedron series,        14, 311-316).    -   iii) The mixture of stereoisomers may be resolved by        conventional methods such as forming a diastereomeric salts with        chiral acids or chiral amines, or chiral amino alcohols, chiral        amino acids. The resulting mixture of diastereomers may then be        separated by methods such as fractional crystallization,        chromatography and the like, which is followed by an additional        step of isolating the optically active product by hydrolyzing        the derivative (Jacques et. al., “Enantiomers, Racemates and        Resolution”, Wiley Interscience, 1981).    -   iv) The mixture of stereoisomers may be resolved by conventional        methods such as microbial resolution, resolving the        diastereomeric salts formed with chiral acids or chiral bases.

Chiral acids that can be employed may be tartaric acid, mandelic acid,lactic acid, camphorsulfonic acid, amino acids and the like. Chiralbases that can be employed may be cinchona alkaloids, brucine or a basicamino acid such as lysine, arginine and the like.

The pharmaceutically acceptable salts forming a part of this inventionmay be prepared by treating the compound of formula (I) with 1-6equivalents of a base such as Lithium, ammonia, substituted ammonia,sodium hydride, sodium methoxide, sodium ethoxide, sodium hydroxide,potassium t-butoxide, calcium hydroxide, calcium acetate, calciumchloride, magnesium hydroxide, magnesium chloride and the like. Solventssuch as water, acetone, ether, THF, methanol, ethanol, t-butanol,dioxane, isopropanol, isopropyl ether or mixtures thereof may be used.Organic bases such lysine, arginine, methyl benzylamine, ethanolamine,diethanolamine, tromethamine, choline, guanidine and their derivativesmay be used. Acid addition salts, wherever applicable may be prepared bytreatment with acids such as tartaric acid, mandelic acid, fumaric acid,maleic acid, lactic acid, salicyclic acid, citric acid, ascorbic acid,benzene sulfonic acid, p-toluene sulfonic acid, hydroxynaphthoic acid,methane sulfonic acid, malic acid, acetic acid, benzoic acid, succinicacid, palmitic acid, oxalic acid, hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid and the like in solvents such as water,alcohols, ethers, ethyl acetate, dioxane, DMF or a lower alkyl ketonesuch as acetone, or the mixtures thereof.

Different polymorphs may be prepared by crystallization of compounds ofgeneral formula (I) under different conditions such as differentsolvents or solvent mixtures in varying proportions forrecrystallization, various ways of crystallization such as slow cooling,fast cooling or a very fast cooling or a gradual cooling duringcrystallization. Different polymorphs may also be obtained by heatingthe compound, melting the compound and solidification by gradual or fastcooling, heating or melting under vacuum or under inert atmosphere andcooling under either vacuum or inert atmosphere. The various polymorphsmay be identified by either one or more of the following techniques suchas differential scanning calorimeter, powder X-ray diffraction, IRspectroscopy, solid probe NMR spectroscopy and thermal microscopy.

Another aspect of the present invention comprises of a pharmaceuticalcomposition, containing at least one of the compounds of the generalformula (I), their derivatives, their tautomeric forms, theirstereoisomers, their geometric forms, their polymorphs, theirpharmaceutically acceptable salts, their pharmaceutically acceptablesolvates thereof as an active ingredient, together with pharmaceuticallyemployed carriers, auxiliaries and the like.

The pharmaceutical compositions of the present invention may beformulated in a conventional manner using one or more pharmaceuticallyacceptable carriers. Thus, the active compounds of the invention may beformulated for oral, buccal, intranasal, parental (e.g., intravenous,intramuscular or subcutaneous) or rectal administration or a formsuitable for administration by inhalation or insufflation.

The dose of the active compounds can vary depending on factors such asthe route of administration, age and weight of patient, nature andseverity of the disease to be treated and similar factors. Therefore,any reference herein to a pharmacologically effective amount of thecompounds of general formula (I) refers to the aforementioned factors.

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents(e.g., pregelatinised maize starch, polyvinylpyrrolidone orhydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystallinecellulose or calcium phosphate); lubricants (e.g., magnesium stearate,talc or silica); disintegrants (e.g., potato starch or sodium starchglycolate); or wetting agents (e.g., sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions, or they may be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.,sorbitol syrup, methyl cellulose or hydrogenated edible fats);emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles(e.g., almond oil, oily esters or ethyl alcohol); and preservatives(e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).

For buccal administration, the composition may take the form of tabletsor lozenges formulated in conventional manner.

The active compounds of the invention may be formulated for parenteraladministration by injection, including using conventionalcatheterization techniques or infusion. Formulations for injection maybe presented in unit dosage form, e.g., in ampoules or in multi-dosecontainers, with an added preservative. The compositions may take suchforms as suspensions, solutions or emulsions in oily or aqueousvehicles, and may contain formulating agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form for reconstitution with a suitablevehicle, e.g., sterile pyrogen-free water, before use.

The active compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g., containingconventional suppository bases such as cocoa butter or other glycerides.

For intranasal administration or administration by inhalation, theactive compounds of the invention are conveniently delivered in the formof an aerosol spray from a pressurized container or a nebulizer, or froma capsule using a inhaler or insufflator. In the case of a pressurizedaerosol, a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas and the dosage unit may be determined by providing avalve to deliver a metered amount. The medicament for pressurizedcontainer or nebulizer may contain a solution or suspension of theactive compound while for a capsule it preferably should be in the formof powder. Capsules and cartridges (made, for example, from gelatin) foruse in an inhaler or insufflator may be formulated containing a powdermix of a compound of the invention and a suitable powder base such aslactose or starch.

A proposed dose of the active compounds of this invention, for eitheroral, parenteral, nasal or buccal administration, to an average adulthuman, for the treatment of the conditions referred to above, is 0.1 to200 mg of the active ingredient per unit dose which could beadministered, for example, 1 to 4 times per day.

Aerosol formulations for treatment of the conditions referred to above(e.g., migraine) in the average adult human are preferably arranged sothat each metered dose or “puff” of aerosol contains 20 μg to 1000 μg ofthe compound of the invention. The overall daily dose with an aerosolwill be within the range 100 μg to 10 mg. Administration may be severaltimes daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or3 doses each time.

The affinities of the compound of this invention for the variousserotonin receptors are evaluated using standard radioligand bindingassays and are described here.

Radioligand Binding Assays for Various 5-ht Receptor Sub-Types:

i) Assay for 5HT_(1A)

Materials and Methods:

-   -   Receptor source: Human recombinant expressed in HEK-293 cells    -   Radioligand: [3H]-8-OH-DPAT (221 Ci/mmol)    -   Final ligand concentration—[0.5 nM]    -   Reference compound: 8-OH-DPAT    -   Positive control: 8-OH-DPAT        Incubation Conditions:

Reactions are carried out in 50 mM TRIS-HCl (pH 7.4) containing 10 mMMgSO₄, 0.5 mM EDTA and 0.1% Ascorbic acid at room temperature for 1hour. The reaction is terminated by rapid vacuum filtration onto glassfiber filters. Radioactivity trapped onto the filters is determined andcompared to control values in order to ascertain any interactions oftest compound with the 5HT_(1A) binding site.

Literature Reference:

-   Hoyer D., Engel G., et al. Molecular Pharmacology of 5HT₁ and 5-HT₂    Recognition Sites in Rat and Pig Brain Membranes: Radioligand    Binding Studies with [³H]-5HT, [³H]-8-OH-DPAT,    [¹²⁵I]-Iodocyanopindolol, [³H]-Mesulergine and [³H]-Ketanserin. Eur.    Jml. Pharmacol. 118: 13-23 (1985) with modifications.-   Schoeffter P. and Hoyer D. How Selective is GR 43175? Interactions    with Functional 5-HT_(1A), 5HT_(1B), 5-HT_(1C), and 5-HT_(1D)    Receptors. Naunyn-Schmiedeberg's Arch. Pharmac. 340: 135-138 (1989)    with modifications.    ii) Assay for 5HT_(1B)    Materials and Methods:    -   Receptor source: Rat striatal membranes    -   Radioligand: [¹²⁵I]Iodocyanopindolol (2200 Ci/mmol)    -   Final ligand concentration—[0.15 nM]    -   Non-specific determinant: Serotonin—[10 μM]    -   Reference compound: Serotonin    -   Positive control: Serotonin        Incubation Conditions:

Reactions are carried out in 50 mM TRIS-HCl (pH 7.4) containing 60 M (−)isoproterenol at 37° C. for 60 minutes. The reaction is terminated byrapid vacuum filtration onto glass fiber filters. Radioactivity trappedonto the filters is determined and compared to control values in orderto ascertain any interactions of test compound with the 5HT_(1B) bindingsite.

Literature Reference:

-   Hoyer D., Engel G., et al. Molecular Pharmacology of 5HT₁ and 5-HT₂    Recognition Sites in Rat and Pig Brain Membranes: Radioligand    Binding Studies with (3H]-5HT, [³H]-8-OH-DPAT,    [¹²⁵I]-Iodocyanopindolol, [³H]-Mesulergine and [³H]-Ketanserin. Eur.    Jml. Pharmacol. 118: 13-23 (1985) with modifications.-   Schoeffter P. and Hoyer D. How selective is GR 43175? Interactions    with Functional 5-HT_(1A), 5HT_(1D), 5-HT_(1C), and 5-HT, Receptors.    Naunyn-Schmiedeberg's Arch. Pharmac. 340: 135-138 (1989) with    modifications.    iii) Assay for ⁵HT_(1D)    Materials and Methods:    -   Receptor source: Human cortex    -   Radioligand: [³H]5-Carboxamidotryptamine (20-70 Ci/mmol)-   Final ligand concentration—[2.0 nM]-   Non-specific determinant: 5-Carboxamidotryptamine (5-CT)—[1.0 μM]-   Reference compound: 5-Carboxamidotryptamine (5-CT)-   Positive control: 5-Carboxamidotryptamine (5-CT)    Incubation Conditions:

Reactions are carried out in 50 mM TRIS-HCl (pH 7.7) containing 4 mMCaCl₂, 100 nM BOH-DPAT, 100 nM Mesulergine, 10 uM Pargyline and 0.1%ascorbic acid at 25° C. for 60 minutes. The reaction is terminated byrapid vacuum filtration onto glass fiber filters. Radioactivity trappedonto the filters is determined and compared to control values in orderto ascertain any interactions of test compound with the cloned 5HT₁₀binding site.

Literature Reference:

-   Waeber C., Schoeffter, Palacios J. M. and Hoyer D. Molecular    Pharmacology of the 5-HT_(1D) Recognition Sites: Radioligand Binding    Studies in Human, Pig, and Calf Brain Membranes.    Naunyn-Schmiedeberg's Arch. Pharmacol. 337: 595-601 (1988) with    modifications.    iv) Assay for 5HT_(2A)    Materials and Methods:    -   Receptor source: Human Cortex    -   Radioligand: [³H] Ketanserin (60-90 Ci/mmol)    -   Final ligand concentration—[2.0 nM]    -   Non-specific determinant: Ketanserin—[3.0 μM]    -   Reference compound: Ketanserin    -   Positive control: Ketanserin        Incubation Conditions:

Reactions are carried out in 50 mM TRIS-HCl (pH 7.5) at room temperaturefor 90 minutes. The reaction is terminated by rapid vacuum filtrationonto glass fiber filters. Radioactivity trapped onto the filters isdetermined and compared to control values in order to ascertain anyinteractions of test compound with the 5HT_(2A) binding site.

Literature Reference:

-   Leysen J. E., Niemegeers C. J., Van Nueten J. M. and Laduron P. M.    [³H]Ketanserin: A Selective Tritiated Ligand for Serotonin₂ Receptor    Binding Sites. Mol. Pharmacol. 21: 301-314 (1982) with    modifications.-   Martin, G. R. and Humphrey, P. P. A. Classification Review:    Receptors for 5-HT: Current Perspectives on Classification and    Nomenclature. Neuropharmacol. 33(3/4): 261-273 (1994).    v) Assay for 5HT_(2C)    Materials and Methods:    -   Receptor source: Pig choroid plexus membranes    -   Radioligand: [³H] Mesulergine (50-60 Ci/mmol)    -   Final ligand concentration—[1.0 nM]    -   Non-specific determinant: Serotonin—[100 μM]    -   Reference compound: Mianserin    -   Positive control: Mianserin        Incubation Conditions:

Reactions are carried out in 50 mM TRIS-HCl (pH 7.7) containing 4 mMCaCl₂ and 0.1% ascorbic acid at 37° C. for 60 minutes. The reaction isterminated by rapid vacuum filtration onto glass fiber filters.Radioactivity trapped onto the filters is determined and compared tocontrol values in order to ascertain any interactions of test compoundwith the 5HT_(2C) binding site.

Literature Reference:

-   A. Pazos, D. Hoyer, and J. Palacios. The Binding of Serotonergic    Ligands to the Porcine Choroid Plexus: Characterization of a New    Type of Serotonin Recognition Site. Eur. Jml. Pharmacol. 106:    539-546 (1985) with modifications.-   Hoyer, D., Engel, G., et al. Molecular Pharmacology of 5HT₁ and    5-HT₂ Recognition Sites in Rat and Pig Brain Membranes: Radioligand    Binding Studies with [3H]-5HT, [3H]-8-OH-DPAT,    [¹²⁵I]-Iodocyanopindolol, [3H]-Mesulergine and [3H]-Ketanserin. Eur.    Jml. Pharmacol. 118: 13-23 (1985) with modifications.    vi) Assay for 5HT₃    Materials and Methods:    -   Receptor source: N1E-115 cells    -   Radioligand: [³H]-GR 65630 (30-70 Ci/mmol)    -   Final ligand concentration—[0.35 nM]    -   Non-specific determinant: MDL-72222—[1.0 μM]    -   Reference compound: MDL-72222    -   Positive control: MDL-72222        Incubation Conditions:

Reactions are carried out in 20 mM HEPES (pH 7.4) containing 150 mM NaClat 25° C. for 60 minutes. The reaction is terminated by rapid vacuumfiltration onto glass fiber filters. Radioactivity trapped onto thefilters is determined and compared to control values in order toascertain any interactions of test compound with the 5HT₃ binding site.

Literature Reference:

-   Lummis S. C. R., Kilpatrick G. J. Characterization of 5HT₃ Receptors    in Intact N1E-115 Neuroblastoma Cells. Eur. Jml. Pharmacol. 189:    223-227 (1990) with modifications.-   Hoyer D. and Neijt H. C. Identification of Serotonin 5-HT₃    Recognition Sites in Membranes of N1E-115 Neuroblastoma Cells by    Radioligand Binding. Mol. Pharmacol. 33: 303 (1988).-   Tyers M. B. 5-HT₃ Receptors and the Therapeutic Potential of 5HT₃    Receptor Antagonists. Therapie. 46:431-435 (1991).    vii) Assay for 5HT₄    Materials and Methods:    -   Receptor source: Guinea pig striatal membranes    -   Radioligand: [³H] GR-113808 (30-70 Ci/mmol)    -   Final ligand concentration—[0.2 nM]    -   Non-specific determinant: Serotonin (5-HT)-[30 μM]    -   Reference compound: Serotonin (5-HT)    -   Positive control: Serotonin (5-HT)        Incubation Conditions:

Reactions are carried out in 50 mM HEPES (pH 7.4) at 370 C. for 60minutes. The reaction is terminated by rapid vacuum filtration ontoglass fiber filters. Radioactivity trapped onto the filters isdetermined and compared to control values in order to ascertain anyinteractions of test compound with the 5-HT₄ binding site.

Literature Reference:

-   Grossman Kilpatrick. C., et al. Development of a Radioligand Binding    Assay for 5HT₄ Receptors in Guinea Pig and Rat Brain. Brit. J    Pharmco. 109: 618-624 (1993).    viii) Assay for 5-HT_(5A)    Materials and Methods:    -   Receptor source: Human recombinant expressed in HEK 293 cells    -   Radioligand: [³H] LSD (60-87 Ci/mmol)    -   Final ligand concentration—[1.0 nM]    -   Non-specific determinant: Methiothepin mesylate—[1.0 μM]    -   Reference compound: Methiothepin mesylate    -   Positive control: Methiothepin mesylate        Incubation Conditions:

Reactions are carried out in 50 mM TRIS-HCl (pH 7.4) containing 10 mMMgSO₄ and 0.5 mM EDTA at 37° C. for 60 minutes. The reaction isterminated by rapid vacuum filtration onto glass fiber filters.Radioactivity trapped onto the filters is determined and compared tocontrol values in order to ascertain any interactions of test compoundwith the cloned 5HT_(5A) binding site.

Literature Reference:

-   Rees S., et al. FEBS Letters, 355: 242-246 (1994) with modifications    ix) Assay for 5HT₆    Materials and Methods:    -   Receptor source: Human recombinant expressed in HEK293 cells    -   Radioligand: [³H]LSD (60-80 Ci/mmol)    -   Final ligand concentration—[1.5 nM]    -   Non-specific determinant: Methiothepin mesylate—[0.1 μM]    -   Reference compound: Methiothepin mesylate    -   Positive control: Methiothepin mesylate        Incubation Conditions:

Reactions are carried out in 50 mM TRIS-HCl (pH 7.4) containing 10 mMMgCl₂, 0.5 mM EDTA for 60 minutes at 37° C. The reaction is terminatedby rapid vacuum filtration onto glass fiber filters. Radioactivitytrapped onto the filters is determined and compared to control values inorder to ascertain any interactions of test compound(s) with the clonedserotonin-5HT₆ binding site.

Literature Reference:

-   Monsma F. J. Jr., et al., Molecular Cloning and Expression of Novel    Serotonin Receptor with High Affinity for Tricyclic Psychotropic    Drugs. Mol. Pharmacol. (43): 320327 (1993).    x) Assay for 5-HT₇    Materials and Methods:    -   Receptor source: Human recombinant expressed in CHO cells    -   Radioligand: (3H]LSD (60-80 Ci/mmol)    -   Final ligand concentration—[2.5 nM]    -   Non-specific determinant: 5-Carboxamidotryptamine (5-CT)-[0.1        μM]    -   Reference compound: 5-Carboxamidotryptamine    -   Positive control: 5-Carboxamidotryptamine        Incubation Conditions:

Reactions are carried out in 50 mM TRIS-HCl (pH 7.4) containing 10 mMMgCl₂. 0.5 mM EDTA for 60 minutes at 37° C. The reaction is terminatedby rapid vacuum filtration onto glass fiber filters. Radioactivitytrapped onto the filters is determined and compared to control values inorder to ascertain any interactions of test compound(s) with the clonedserotonin—5HT₇ binding site.

Literature Reference:

-   Y. Shen, E. Monsma, M. Metcalf, P. Jose, M Hamblin, D. Sibley,    Molecular Cloning and Expression of a 5-hydroxytryptamine7 Serotonin    Receptor Subtype. J. Biol. Chem. 268: 18200-18204.

The following description illustrates the method of preparation ofvariously substituted compounds of general formula (I), according to themethods described herein. These are provided by the way of illustrationonly and therefore should not be construed to limit the scope of theinvention.

Commercial reagents were utilized without further purification. Roomtemperature refers to 25-30° C. Melting points are uncorrected. IRspectra were taken using KBr and in solid state. Unless otherwisestated, all mass spectra were carried out using ESI conditions. ¹H NMRspectra were recorded at 300 MHz on a Bruker instrument. Deuteratedchloroform (99.8% D) was used as solvent TMS was used as internalreference standard. Chemical shift values are expressed in are reportedin parts per million (6)-values. The following abbreviations are usedfor the multiplicity for the NMR signals: s=singlet, bs=broad singlet,d=doublet, t=triplet, q=quartet, qui=quintet, h=heptet, dd=doubledoublet, dt=double triplet, tt=triplet of triplets, m=multiplet. NMR,mass were corrected for background peaks. Specific rotations weremeasured at room temperature using the sodium D (0.589 nm).Chromatography refers to column chromatography performed using 60-120mesh silica gel and executed under nitrogen pressure (flashchromatography) conditions.

Description 1: N,N-Dimethyl-1-(2′-bromobenzoyl)tryptamine (D1)

A suspension of potassium hydride (15.0 mmoles, 2.0 g. (30% suspensionin mineral oil), washed with THF before use), in 30 mL of THF wasstirred and cooled at 10° C. To this cooled solution was added asolution of N,N-dimethyltryptamine (15 mmoles), in THF, slowly, over 15min., maintaining the temperature below 10° C. After that a solution of2-bromobenzoyl chloride in THF (15 mmoles, in 10 mL of THF) was thenadded under nitrogen blanket and the reaction temperature was maintainedbelow 10° C. (Exothermic reaction). Further, the reaction mixture wasmaintained at 20-25° C. for further 2-4 hrs. After completion ofreaction (TLC), the excess of THF was distilled off and the concentratewas diluted with ice-water and extracted with ethyl acetate. Combinedethyl acetate layer was washed with water, dried over sodium sulfate andevaporated under reduced pressure, below 50° C.

The crude residue was purified by silica gel column chromatography using30% methanol in ethyl acetate as a mobile phase, to obtain theintermediate, N,N-Dimethyl-1-(2¹ bromobenzoyl)tryptamine, which wasidentified by IR, NMR and mass spectral analyses.

Description 2-21 (D2-D21)

Various indole intermediates were reacted with substituted2-bromobenzoyl chloride according to the procedure described in thedescription 1. These compounds were identified by IR, NMR and massspectral analyses. The following list includes list of such compounds.

List-1: Description Mass ion (M + H)⁺ D12-[1-(2-Bromobenzoyl)indol3-yl]ethyl-N,N-dimethylamine 371 D22-[1-(2-Bromobenzoyl)-5-bromoindol3-yl]ethyl-N,N-dimethylamine 449 D32-[1-(2-Bromobenzoyl)-5-chloroindol3-yl]ethyl-N,N-dimethylamine 405 D42-[1-(2-Bromobenzoyl)-5-fluoroindol3-yl]ethyl-N,N-dimethylamine 389 D52-[1-(2-Bromobenzoyl)-5-methylindol3-yl]ethyl-N,N-dimethylamine 385 D62-[1-(2-Bromobenzoyl)-5-methoxyindol3-yl]ethyl-N,N-dimethylamine 401 D72-[1-(2-Bromobenzoyl)-7-ethylindol3-yl]ethyl-N,N-dimethylamine 399 D82-[1-(2-Bromobenzoyl)-7-chloroindol3-yl]ethyl-N,N-dimethylamine 405 D92-[1-(2-Bromobenzoyl)-7-methoxyindol3-yl]ethyl-N,N-dimethylamine 401 D102-[1-(2-Bromobenzoyl)-7-trifluoromethylindol3-yl]ethyl-N,N- 439dimethylamine D112-[1-(2-Bromobenzoyl)-5,7-dichloroindol3-yl]ethyl-N,N-dimethylamine 439D12 2-[1-(2-Bromobenzoyl)-6,7-dichloroindol3-yl]ethyl-N,N-dimethylamine439 D132-[1-(2-Bromobenzoyl)-5,7-difluoroindol3-yl]ethyl-N,N-dimethylamine 407D14 2-[1-(2-Bromobenzoyl)-5,7-dimethylindol3-yl]ethyl-N,N-dimethylamine399 D152-[1-(2-Bromobenzoyl)-6,7-dimethylindol3-yl]ethyl-N,N-dimethylamine 399D16 2-[1-(2-Bromobenzoyl)-4-chloro-7-methylindol3-yl]ethyl-N,N- 419dimethylamine D172-[1-(2-Bromobenzoyl)-6-chloro-7-methylindol3-yl]ethyl-N,N- 419dimethylamine D182-[1-(2-Bromobenzoyl)-4,5,7-trichloroindol3-yl]ethyl-N,N-dimethylamine473 D19 2-[1-(2-Bromobenzoyl)indol3-yl]-1-hydroxyethyl-N,N-dimethylamine387 D201-(2-Bromobenzoyl)-5-bromo-3-(2-(morpholino-1-yl)ethyl)-1H-indole 491D21 1-(2-Bromobenzoyl)-(2-(4-methyl-piperazin-1-yl)ethyl)-1H-indole 504

EXAMPLE-1 11-(2-N,N-Dimethylaminoethyl)isoindolo[2,1-a]indol-6-one

1-(2′-bromobenzoyl)-N,N-dimethyltryptamine (0.286 moles) was taken in a100 mL 3 necked round bottomed flask, along with N,N-dimethyl acetamide(40 mL), potassium acetate (0.286 moles, 0.281 g.) and dichlorobis(tri-o-tolylphosphine)palladium (0.0143 moles, 0.0126 g.). Thereaction mixture was maintained under nitrogen atmosphere and was heatedto 160° C. with stirring for 16 hrs. After the completion of reaction(TLC), excess of dimethyl acetamide was distilled off under reducedpressure.

The residue obtained was purified by silica gel column chromatographyusing 20% methanol in ethyl acetate as an eluent, to afford the titlecompound, which was identified by IR, NMR and mass spectral analyses.The final desired compound of general formula (I) can be furtherpurified by preparation of their acid addition salts. IR spectra (cm⁻¹):2939, 2779, 1721, 1446; Mass (m/z): 291 (M+H)⁺; ¹H-NMR (δ ppm): 2.38(6H, s), 2.57-2.69 (2H, m), 3.00-3.10 (2H, m), 7.12-7.90 (8H, m).

EXAMPLE-211-[(2-N,N-Dimethylaminoethyl]-2-fluoroisoindolo[2,1-a]indol-6-one

Using essentially the general procedure described in example 1 and somenon-critical variations, the above derivative was prepared. Meltingrange (° C.): 112-117; IR spectra (cm⁻¹): 2940, 2780, 1730, 1466, 1446;Mass (m/z): 309 (M+H)⁺; ¹H-NMR (δ ppm) 2.36 (6H, s), 2.57-2.65 (2H, m),2.95-3.00 (2H, m), 6.93-7.81 (7H, m).

EXAMPLE-311-[(2-N,N-Dimethylamino)ethyl]-2-fluoroisoindolo[2,1-a]indol-6-onehydrochloride salt

Example no. 2 (199 mg) was dissolved in 30 mL ether. To this clearsolution a mixture of isopropylalcohol-hydrochloric acid (10 mL) wasadded. Immediately a white precipitate separates out, which wasfiltered, washed with ether and dried. Melting range (° C.): >250 (dec).

EXAMPLE-411-[(2-N,N-Dimethylamino)ethyl]-2-fluoroisoindolo[2,1-a]indol-6-onemaleic acid salt

Example no. 2 (205 mg) was dissolved in 30 mL ether. To this clearsolution a solution of maleic acid (82 mg, dissolved in 30 mL ether+5 mLmethanol) was added. Immediately a white precipitate separates out,which was filtered, washed with ether and dried. Melting range (° C.):180-182 (dec).

EXAMPLE-511-[(2-N,N-Dimethylamino)ethyl]-2-fluoroisoindolo[2,1-a]indol-6-oneD,L-malic acid salt

Example no. 2 (208 mg) was dissolved in 30 mL ether. To this clearsolution a solution of D,L-malic acid (106 mg, dissolved in 30 mLether+5 mL methanol) was added. Immediately a white precipitateseparates out, which was filtered, washed with ether and dried. Meltingrange (° C.): 170-173.

EXAMPLE-611-[(2-N,N-Dimethylamino)ethyl]-2-fluoroisoindolo[2,1-a]indol-6-oneoxalate salt

Example no. 2 (203 mg) was dissolved in 30 mL ether. To this clearsolution a solution of oxalic acid (94 mg, dissolved in 30 mL ether+5 mLmethanol) was added. Immediately a white precipitate separates out,which was filtered, washed with ether and dried. Melting range (° C.):244-246 (dec).

EXAMPLE-711-[(2-N,N-Dimethylamino)ethyl]-2-fluoroisoindolo[2,1-a]indol-6-onecitrate salt

Example no. 2 (201 mg) was dissolved in 30 mL ether. To this clearsolution a solution of citric acid (134 mg, dissolved in 30 mL ether+5mL methanol) was added. Immediately a white precipitate separates out,which was filtered, washed with ether and dried. Melting range (° C.):178-180.

EXAMPLE-82-Bromo-11-[(2-N,N-dimethylamino)ethyl]isoindolo[2,1-a]indol-6-one

Using essentially the general procedure described in example 1 and somenon-critical variations, the above derivative was prepared. Meltingrange (° C.): 118-121; IR spectra (cm⁻¹): 2942, 2759, 1718, 1444, 882,761; Mass (m/z): 369 (M+H)⁺, 371 (M+3)⁺; ¹H-NMR (δ ppm): 2.36 (6H, s),2.57-2.65 (2H, m), 2.95-3.00 (2H, m), 7.29-7.77 (7H, m).

EXAMPLE-92-Chloro-11-[(2-N,N-dimethylamino)ethyl]isoindolo[2,1-a]indol-6-one

Using essentially the general procedure described in example 1 and somenon-critical variations, the above derivative was prepared. IR spectra(cm⁻¹): 2925, 2765, 1723, 1446, 1381, 758, 700; Mass (m/z): 325 (M+H)⁺;¹H-NMR (δ ppm): 2.32 (6H, s), 2.54-2.62 (2H, m), 2.76-2.84 (2H, m),7.27-7.73 (7H, m).

EXAMPLE-104-Chloro-11-[(2-N,N-dimethylamino)ethyl]isoindolo[2,1-a]indol-6-one

Using essentially the general procedure described in example 1 and somenon-critical variations, the above derivative was prepared. IR spectra(cm⁻¹): 2942, 2779, 1746, 1417, 1343, 782, 700; Mass (m/z): 325 (M+H)⁺;¹H-NMR (δ ppm): 2.90 (6H, s), 3.27-3.31 (2H, m), 3.52-3.57 (2H, m),7.07-8.09 (7H, m).

EXAMPLE-1111-[(2-N,N-Dimethylamino)ethyl]-2-methylisoindolo[2,1-a]indol-6-one

Using essentially the general procedure described in example 1 and somenon-critical variations, the above derivative was prepared. Meltingrange (° C.): 116-128; IR spectra (cm⁻¹): 2941, 2761, 1714, 1611, 1468;Mass (m/z): 305 (M+H)⁺; ¹H-NMR (δ ppm) 2.39 (6H, s), 2.42 (3H, s),2.57-2.76 (2H, m), 2.99-3.07 (2H, m), 7.07-7.67 (7H, m).

EXAMPLE-1211-[(2-N,N-Dimethylamino)ethyl]-2-methoxyisoindolo[2,1-a]indol-6-one

Using essentially the general procedure described in example 1 and somenon-critical variations, the above derivative was prepared. IR spectra(cm⁻¹): 2941, 2773, 1466, 1371, 1237; Mass (m/z): 321 (M+H)⁺; ¹H-NMR (δppm): 2.39 (6H, s), 2.60-2.68 (2H, m), 2.98-3.06 (2H, m), 3.85 (3H, s),6.84-7.66 (7H, m).

EXAMPLE-1311-[(2-N,N-Dimethylamino)ethyl]2-methoxyisoindolo[2,1-a]indol-6-one

Using essentially the general procedure described in example 1 and somenon-critical variations, the above derivative was prepared. IR spectra(cm⁻¹): 2941, 2773, 1728, 1466, 1230; Mass (m/z): 321 (M+1H)⁺.

EXAMPLE-1411-[(2-N,N-Dimethylamino)ethyl]-4-trifluoromethylisoindolo[2,1-a]indol-6-one

Using essentially the general procedure described in example 1 and somenon-critical variations, the above derivative was prepared. Mass (m/z):359 (M+H)⁺.

EXAMPLE-1511-[(2-N,N-Dimethylamino)ethyl]-4-ethylisoindolo[2,1-a]indol-6-one

Using essentially the general procedure described in example 1 and somenon-critical variations, the above derivative was prepared. Mass (m/z):319 (M+H)⁺.

EXAMPLE-1611-[(2-N,N-Dimethylamino)ethyl]-2,4-difluoroisoindolo[2,1-a]indol-6-one

Using essentially the general procedure described in example 1 and somenon-critical variations, the above derivative was prepared. Mass (m/z):327 (M+H)⁺.

EXAMPLE-172,4-Dichloro-11-[(2-N,N-dimethylamino)ethyl]isoindolo[2,1-a]indol-6-one

Using essentially the general procedure described in example 1 and somenon-critical variations, the above derivative was prepared. Mass (m/z):359 (M+H)⁺.

EXAMPLE-183,4-Dichloro-11-[(2-N,N-dimethylamino)ethyl]isoindolo[2,1-a]indol-6-one

Using essentially the general procedure described in example 1 and somenon-critical variations, the above derivative was prepared. Mass (m/z):359 (M+H)⁺.

EXAMPLE-191,2,4-Trichloro-11-[(2-N,N-dimethylamino)ethyl]isoindolo[2,1-a]indol-6-one

Using essentially the general procedure described in example 1 and somenon-critical variations, the above derivative was prepared. Mass (m/z):393 (M+H)⁺.

EXAMPLE-2011-[(2-N,N-Dimethylamiethythyl]-2,4-dimethylisoindolo[2,1-a]indol-6-one

Using essentially the general procedure described in example 1 and somenon-critical variations, the above derivative was prepared. Meltingrange (° C.): 100-102; IR spectra (cm⁻¹): 2942, 2758, 1721, 1449, 1242;Mass (m/z): 319 (M+H)⁺; ¹H-NMR (δ ppm): 2.36 (3H, s), 2.38 (6H, s),2.61-2.65 (2H, m), 2.84 (3H, m), 2.97-3.00 (2H, s), 6.87-7.75 (6H, m).

EXAMPLE-2111-[(2-N,N-Dimethylamino)ethyl]-3,4-dimethylisoindolo[2,1-a]indol-6-one

Using essentially the general procedure described in example 1 and somenon-critical variations, the above derivative was prepared. Meltingrange (° C.): 119-121; IR spectra (cm⁻¹): 2941, 2762, 1719, 1305; Mass(m/z): 319 (M+H)⁺; ¹H-NMR (δ ppm): 2.35 (3H, s), 2.38-2.40 (6H, s),2.61-2.65 (2H, m), 2.86 (3H, m), 2.98-3.06 (2H, s), 6.98-7.76 (6H, m).

EXAMPLE-221-Chloro-11-[(2-N,N-dimethylamino)ethyl]-4-methylisoindolo[2,1-a]indol-6-one

Using essentially the general procedure described in example 1 and somenon-critical variations, the above derivative was prepared. Mass (m/z):339 (M+H)⁺.

EXAMPLE-233-Chloro-1-[(2-N,N-dimethylamino)ethyl]-4-methylisoindolo[2,1-a]indol-6-one

Using essentially the general procedure described in example 1 and somenon-critical variations, the above derivative was prepared. Mass (m/z):339 (M+H)⁺.

EXAMPLE-2411-[(2-N,N-Dimethylamino)propyl]-4-methylisoindolo[2,1-a]indol-6-one

Using essentially the general procedure described in example 1 and somenon-critical variations, the above derivative was prepared. Mass (m/z):305 (M+H)⁺.

EXAMPLE-252-Bromo-11-[(2-morpholin-1-yl)ethyl]isoindolo[2,1-a]indol-6-one

Using essentially the general procedure described in example 1 and somenon-critical variations, the above derivative was prepared. Meltingrange (° C.): 148-151; IR spectra (cm⁻¹): 2956, 2806, 1733, 1438, 1360;Mass (m/z): 411 (M+H)⁺; ¹H-NMR (δ ppm) 2.56-2.63 (4H, t), 2.63-2.71 (2H,m), 2.98-3.06 (2H, m), 3.74-3.78 (4H, t), 7.31-7.79 (7H, m).

EXAMPLE-262-Bromo-11-[2-(4-methylpiperazin-1-yl)ethyl]isoindolo[2,1-a]indol-6-one

Using essentially the general procedure described in example 1 and somenon-critical variations, the above derivative was prepared. Meltingrange (° C.): 146-150; IR spectra (cm⁻¹): 2940, 2790, 1725, 1440, 1357,801, 703; Mass (m/z): 424 (M+H)⁺; ¹H-NMR (δ ppm): 2.28-2.32 (3H, t),2.52-2.75 (10H, m), 2.98-3.05 (2H, m), 7.30-7.78 (7H, m).

1. A compound of the general formula (I),

its tautomeric forms, its stereoisomers, its polymorphs, itspharmaceutically acceptable salts and solvates, wherein R₁, R₂, R₃, R₄,R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁ and R₁₂ may be same or different and eachindependently represent hydrogen, halogen, perhaloalkyl, substituted orunsubstituted groups such as linear or branched (C₁-C₃)alkyl,(C₃-C₇)cycloalkyl, (C₁-C₃)alkoxy, cyclo(C₃-C₇)alkoxy, aryl, aryloxy,aralkyl, aralkoxy, heterocyclyl, acyl, acyloxy, acylamino,monoalkylamino, dialkylamino, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, alkylthio, sulfonic acids and its derivatives, R₁₃ andR₁₄ may be same or different and each independently represents hydrogen,substituted or unsubstituted groups such as linear or branched(C₁-C₃)alkyl, (C₃-C₇)cycloalkyl, optionally R₁₃ and R₁₄ along with thenitrogen atom, may form a 6 or 7-membered heterocyclic ring, wherein thering may be further substituted, and it may have either one, two orthree double bonds or “additional heteroatoms”, as defined above. “n” isan integer ranging from 1 to
 2. It is preferred that n be
 1. 2. Acompound according to claim-1, which is selected from the groupconsisting of: 11-(2-N,N-Dimethylaminoethyl)isoindolo[2,1-a]indol-6-one;11-[(2-N,N-Dimethylamino)ethyl]-2-fluoroisoindolo[2,1-a]indol-6-one;11-[(2-N,N-Dimethylamino)ethyl]-2-fluoroisoindolo[2,1-a]indol-6-onehydrochloride salt;11-[(2-N,N-Dimethylamino)ethyl]-2-fluoroisoindolo[2,1-a]indol-6-onemaleic acid salt:11-[(2-N,N-Dimethylamino)ethyl]-2-fluoroisoindolo[2,1-a]indol-6-oneD,L-malic acid salt;11-[(2-N,N-Dimethylamino)ethyl]-2-fluoroisoindolo[2,1-a]indol-6-oneoxalate salt; 11-[(2-N,N-Dimethylamino)ethyl]-2-fluoroisoindolo[2,1-a]indol-6-one citrate salt;11-[(2-N-cyclopropyl-N-methylamino)ethyl]-2-fluoroisoindolo[2,1-a]indol-6-one;11-[2-N-cyclopropylaminoethyl]-2-fluoroisoindolo[2,1-a]indol-6-one;2-Bromo-11-[(2-N,N-dimethylamino)ethyl]isoindolo[2,1-a]indol-6-one;2-Chloro-11-[(2-N,N-dimethylamino)ethyl]isoindolo[2,1-a]indol-6-one;4-Chloro-11-[(2-N,N-dimethylamino)ethyl]isoindolo[2,1-a]indol-6-one;11-[(2-N,N-Dimethylamino)ethyl]-2-methylisdindolo[2,1-a]indol-6-one;11-[(2-N,N-Dimethylamino)ethyl]-2-methoxyisoindolo[2,1-a]indol-6-one;11-[(2-N,N-Dimethylamino)ethyl]4-methoxyisoindolo[2,1-a]indol-6-one;11-[(2-N,N-Dimethylamino)ethyl]-4-trifluoromethylisoindolo[2,1-a]indol-6-one;11-[(2-N,N-Dimethylamino)ethyl]-4-ethylisoindolo[2,1-a]indol-6-one;11-[(2-N,N-Dimethylamino)ethyl]-2,4-difluoroisoindolo[2,1-a]indol-6-one;2,4-Dichloro-11-[(2-N,N-dimethylamino)ethyl]isoindolo[2,1-a]indol-6-one,3,4-Dichloro-11-[(2-N,N-dimethylamino)ethyl]isoindolo[2,1-a]indol-6-one;1,2,4-Trichloro-11-[(2-N,N-dimethylamino)ethyl]isoindolo[2,1-a]indol-6-one;11-[(2-N,N-Dimethylamino)ethyl]-2,4-dimethylisoindolo[2,1-a]indol-6-one;11-[(2-N,N-Dimethylamino)ethyl]-3,4-dimethylisoindolo[2,1-a]indol-6-one;1-Chloro-11-[(2-N,N-dimethylamino)ethyl]-4-methylisoindolo[2,1-a]indol-6-one;3-Chloro-11-[(2-N,N-dimethylamino)ethyl]-4-methylisoindolo[2,1-a]indol-6-one;11-[(2-N,N-Dimethylamino)propyl]4-methylisoindolo[2,1-a]indol-6-one;3-Chloro-11-[(2-N-methylamino)ethyl]-4-methylisoindolo[2,1-a]indol-6-one;3-Chloro-11-[(2-N-methyl-N-acetylamino)ethyl]methylisoindolo[2,1-a]indol-6-one;3-Chloro-11-[(2-N-methylamino)ethyl]-2-methoxyisoindolo[2,1-a]indol-6-one;3-Chloro-11-[(2-N-methylamino)ethyl]-2-sulfoamidoisoindolo[2,1-a]indol-6-one;3-Iodo-11-[(2-N-methylamino)ethyl]-2-methoxyisoindolo[2,1-a]indol-6-one;2-Bromo-11-[(2-morpholin-1-yl)ethyl]isoindolo[2,1-a]indol-6-one;2-Bromo-11-[2-(4-methylpiperazin-1-yl)ethyl]isoindolo[2,1-a]indol-6-one;and its stereoisomers, its N-oxides, its polymorphs, itspharmaceutically acceptable salts and solvates.
 3. A pharmaceuticalcomposition comprising either of a pharmaceutically acceptable carrier,diluent/s, excipients or solvates along with a therapeutically effectiveamount of a compound according to claim-1, its tautomeric forms, itsstereoisomers, its geometric forms, its N-oxides, its polymorphs, itspharmaceutically acceptable salts, or solvates.
 4. A pharmaceuticalcomposition according to claim-3, in the form of a tablet, capsule,powder, lozenges, suppositories, syrup, solution, suspension orinjectable, administered in, as a single dose or multiple dose units. 5.Use of compound of general formula (I), as defined in claim-1 or apharmaceutical composition as defined in claim-3 for preparingmedicaments.
 6. Use of compound of general formula (I), as defined inclaim-1 or a pharmaceutical composition as defined in claim-3 for thetreatment where a modulation of 5-HT activity is desired.
 7. Use of acompound as claimed in claim-1 for the manufacture of a medicament forthe treatment and/or prevention of clinical conditions for which aselective action on 5-HT receptors is indicated.
 8. Use of a compound asclaimed in claim-1 for the treatment and/or prevention of clinicalconditions such as anxiety, depression, convulsive disorders,obsessive-compulsive disorders, migraine headache, cognitive memorydisorders, ADHD (Attention Deficient Disorder/Hyperactivity Syndrome),personality disorders, psychosis, paraphrenia, psychotic depression,mania, schizophrenia, schizophreniform disorders, withdrawal from drugabuse, panic attacks, sleep disorders and also disorders associated withspinal trauma and/or head injury.
 9. Use of a compound as claimed inclaim-1 for the treatment of mild cognitive impairment and otherneurodegenerative disorders like Alzheimer's disease, Parkinsonism andHuntington's chorea.
 10. Use of a compound as claimed in claim-1 for thetreatment of certain GI (Gastrointestinal) disorders such as IBS(Irritable bowel syndrome) or chemotherapy induced emesis.
 11. Use of acompound as claimed in claim-1 to reduce morbidity and mortalityassociated with the excess weight.
 12. Use of a radiolabelled compoundas claimed in claim-1, as a diagnostic tool for modulating 5-HT receptorfunction.
 13. Use of a compound as claimed in claims 1 in combinationwith a 5-HT re-uptake inhibitor, and/or a pharmaceutically acceptablesalt thereof.
 14. A compound of the general formula (I), its tautomericforms, its stereoisomers, its polymorphs, its pharmaceuticallyacceptable salts and its pharmaceutically acceptable solvates forpreparing a medicament.
 15. A method for the treatment and/orprophylaxis of clinical conditions such as anxiety, convulsivedisorders, obsessive-compulsive disorders, migraine headache, cognitivememory disorders, ADHD (Attention Deficient Disorder/HyperactivitySyndrome), personality disorders, psychosis, paraphrenia, psychoticdepression, mania, schizophrenia, schizophreniform disorders, withdrawalfrom drug abuse, panic attacks, sleep disorders and also disordersassociated with spinal trauma and/or head injury which comprisesadministering to a patient in need thereof, an effective amount of acompound of general formula (I) as claimed in claim-1.
 16. A method forthe treatment and/or prophylaxis of mild cognitive impairment and otherneurodegenerative disorders like Alzheimer's disease, Parkinsonism andHuntington's chorea which comprises administering to a patient in needthereof, an effective amount of a compound of general formula (I) asclaimed in claim-1.
 17. A method for the treatment of certain GI(Gastrointestinal) disorders such as IBS (Irritable bowel syndrome) orchemotherapy induced emesis using a compound of general formula (I) asclaimed in claim-1.
 18. A method to reduce morbidity and mortalityassociated with the excess weight using a compound of general formula(I) as claimed in claim-1.
 19. A process for the preparation of acompound of general formula (I), as defined in claim 1, which comprisesof any one of the following routes, Route i): cyclizing a compound offormula (II) given below,

wherein X is halogen such chloro, bromo or iodo, R₁, R₂, R₃, R₄, R₅, R₆,R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ and “n”, wherein all the symbols areas defined above, using a Pd(0) or Pd (II) derivative as a catalyst;Route ii): reacting a compound (III) given below,

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂ and “n” are asdefined above, with a suitable alkylating agent such as R₁₃ X or R₁₄ Xor XR₁₃R₁₄X in successive steps or in one step, wherein X is goodleaving group such as halogen and hydroxyl; Route iii): reacting acompound of (IV) given below,

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇ and R₈ are as defined above, withformaldehyde and a compound of formula (V) given below,NHR₁₃R₁₄  (V) wherein R₁₃ and R₁₄ are as defined above Route iv): eitherchemically or catalytically reducing compounds containing —C(═O) group/sin the side chain, to the corresponding —C(OH,H) or —C(H,H) compound.20. A process according to claim-19 comprising of carrying out one ormore of the following optional steps: i) removing any protecting group;ii) resolving the racemic mixture into pure enantiomers by the knownmethods and iii) preparing a pharmaceutically acceptable salt of acompound of formula (I) and/or iv preparing a pharmaceuticallyacceptable prodrug thereof.
 21. Novel intermediates defined of generalformula (IV),

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇ and R₈ are as may be same ordifferent and each independently represent hydrogen, halogen,perhaloalkyl, substituted or unsubstituted groups such as linear orbranched (C₁-C₃)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₃)alkoxy,cyclo(C₃-C₇)alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,acyl, acyloxy, acylamino, monoalkylamino, dialkylamino, hydroxyalkyl,alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, sulfonic acids andits derivatives.
 22. A process provided for the preparation of novelintermediate of the general formula (IV) which comprises of cyclizingcompounds of formula (VIII)

wherein, R₁, R₂, R₃, R₄, R₅, R₆, R₇ and R₈ are as defined above; X ishalogeno such as chloro, bromo or iodo, using a Pd(0) or Pd (II)derivative as a catalyst.